Pro-opiomelanocortin (POMC) derived peptides are known to affect food intake. Several lines of evidence support the notion that the G-protein coupled receptors (GPCRs) of the melanocortin receptor (MC-R) family, several of which are expressed in the brain, are the targets of POMC derived peptides involved in the control of food intake and metabolism. A specific single MC-R that may be targeted for the control of obesity has not yet been identified, although evidence has been presented that MC-4R signalling is important in mediating feeding behavior (S. Q. Giraudo et al., “Feeding effects of hypothalamic injection of melanocortin-4 receptor ligands,” Brain Research, 80: 302-306 (1998)).
Five distinct MC-R's have thus far been identified, and these are expressed in different tissues. MC-1R was initially characterized by dominant gain of function mutations at the Extension locus, affecting coat color by controlling phaeomelanin to eumelanin conversion through control of tyrosinase. MC-1R is mainly expressed in melanocytes. MC-2R is expressed in the adrenal gland and represents the ACTH receptor. MC-3R is expressed in the brain, gut, and placenta and may be involved in the control of food intake and thermogenesis. MC-4R is uniquely expressed in the brain, and its inactivation was shown to cause obesity (A. Kask, et al., “Selective antagonist for the melanocortin-4 receptor (HS014) increases food intake in free-feeding rats,” Biochem. Biophys. Res. Commun., 245: 90-93 (1998)). MC-5R is expressed in many tissues, including white fat, placenta and exocrine glands. A low level of expression is also observed in the brain. MC-5R knockout mice reveal reduced sebaceous gland lipid production (Chen et al., Cell, 91: 789-798 (1997)).
Evidence for the involvement of MC-R's in obesity includes: i) the agouti (Avy) mouse which ectopically expresses an antagonist of the MC-1R, MC-3R and MC-4R is obese, indicating that blocking the action of these three MC-R's can lead to hyperphagia and metabolic disorders; ii) MC-4R knockout mice (D. Huszar et al., Cell, 88: 131-141 (1997)) recapitulate the phenotype of the agouti mouse and these mice are obese; iii) the cyclic heptapeptide MT-II (a non-selective MC-1R, -3R, -4R, and -5R agonist), when injected intracerebroventricularly (ICV) in rodents, reduces food intake in several animal feeding models (NPY, ob/ob, agouti, fasted) while ICV injected SHU-9119 (MC-3R and 4R antagonist; MC-1R and -5R agonist) reverses this effect and can induce hyperphagia; iv) chronic intraperitoneal treatment of Zucker fatty rats with an α-NDP-MSH derivative (HP228) has been reported to activate MC-1R, -3R, -4R, and -5R and to attenuate food intake and body weight gain over a 12-week period (I. Corcos et al., “HP228 is a potent agonist of melanocortin receptor-4 and significantly attenuates obesity and diabetes in Zucker fatty rats,” Society for Neuroscience Abstracts, 23: 673 (1997)). The appetite suppressing effect of MT-II is no longer observed in mice lacking the MC-4R (D. J. Marsh, et al., “Response of melanocortin-4 receptor-deficient mice to anorectic and orexigenic peptides,” Nat. Genet., 21: 119-122 (1999)).
Based on the above observations, the melanocortin system in the brain is thought to play a crucial role in regulating feeding and energy balance and that MC-4R agonists are considered to be useful for the treatment of obesity. Reference is made to the following publications for a discussion of the involvement of the MC-4R in the central regulation of feeding behavior and body weight and the potential of MC-4R agonists for the treatment of obesity: (1) J. Wikberg, et al., “New aspects of the melanocortins and their receptors,” Pharmacological Res., 42: 393-420 (2000); (2) J. Wikberg, “Melanocortin receptors: new opportunities in drug discovery,” Exp. Opin. Ther. Patents, 11: 61-76 (2001); (3) P. M. Andersson, et al., “Ligands to the melanocortin receptors,” Exp. Opin. Ther. Patents, 11: 1583-1592 (2001); (4) S. Chaki and A. Nakazato, “Recent advances in feeding suppressing agents: potential therapeutic strategy for the treatment of obesity,” Exp. Opin. Ther. Patents, 11: 1677-1692 (2001).
Melanocortin receptor involvement in male and female sexual dysfunction has also been reported. Erectile dysfunction denotes the medical condition of inability to achieve penile erection sufficient for successful sexual intercourse. The term “impotence” is oftentimes employed to describe this prevalent-condition. Synthetic melanocortin receptor agonists (melanotropic peptides) have been found to initiate erections in men with psychogenic erectile dysfunction [See H. Wessells et al., “Synthetic Melanotropic Peptide Initiates Erections in Men With_Psychogenic Erectile Dysfunction: Double-Blind, Placebo Controlled Crossover Study,” J. Urol., 160: 389-393 (1998); Fifteenth American Peptide Symposium, Jun. 14-19, 1997 (Nashville Tenn.)]. In the above study, the centrally acting α-melanocyte-stimulating hormone analog, melanotan-II (M-II), exhibited a 75% response rate, similar to results obtained with apomorphine, when injected intramuscularly or subcutaneously to males with psychogenic erectile dysfunction. MT-II is a synthetic cyclic heptapeptide, Ac-Nle-c[Asp-His-DPhe-Arg-Trp-Lys]-NH2, which contains the 4-10 melanocortin receptor binding region common to α-MSH and adrenocorticotropin, but with a lactam bridge. It is a non-selective MC-1R, -3R, -4R, and -5R agonist (Dorr et al., Life Sciences, Vol. 58, 1777-1784, 1996). MT-II (also referred to as PT-14) (Erectide®) is presently in clinical development by Palatin Technologies, Inc. and TheraTech, Inc. as a non-penile subcutaneous injection formulation. It is considered to be an “initiator” of the sexual response.
Compositions of melanotropic peptides and methods for the treatment of psychogenic erectile dysfunction are disclosed in U.S. Pat. No. 5,576,290, assigned to Competitive Technologies. Methods of stimulating sexual response in females using melanotropic peptides have been disclosed in U.S. Pat. No. 6,051,555.
Spiropiperidine and piperidine derivatives have been disclosed in WO 99/64002 (16 Dec. 1999); WO 00/74679 (14 Dec. 2000); WO 01/70708 (27 Sep. 2001); WO 01/70337 (27 Sep. 2001); WO 01/91752 (6 Dec. 2001); WO 02/15909 (28 Feb. 2002); WO 02/59095 (1 Aug. 2002); U.S. Pat. No. 6,294,534 (25 Sep. 2001); U.S. Pat. No. 6,350,760 (26 Feb. 2002) and U.S. Pat. No. 6,458,790 (1 Oct. 2002) as agonists of the melanocortin receptor(s) and particularly as selective agonists of the MC-4R receptor and their utility for the treatment of obesity and diabetes, and sexual dysfunction, including erectile dysfunction and female sexual dysfunction. Analogous piperazine and piperidine derivatives as melanocortin receptor agonists for the treatment of obesity and diabetes have been disclosed in WO 02/59107 (1 Aug. 2002); WO 02/59108 (1 Aug. 2002); and WO 02/59117 (1 Aug. 2002); and WO 02/068387 (6 Sep. 2002); WO 02/068388 (6 Sep. 2002); WO 03/007949 (30 Jan. 2003); WO 03/009847 (6 Feb. 2003); and WO 03/31410.
There exists a continuing need for potent and receptor-subtype selective MC-4R agonists with improved pharmacodynamnic and pharmacokinetic properties for the treatment, control, or prevention of obesity and diabetes. In particular, there is a need for potent and receptor-subtype selective MC-4R agonists useful for the treatment, control, or prevention of obesity and diabetes, but with diminished erectogenic properties.
It is therefore an object of the present invention to provide piperazine urea derivatives which are melanocortin-4 receptor (MC-4R) agonists useful for the treatment, control, or prevention of obesity and diabetes.
It is another object of the present invention to provide piperazine urea derivatives which are receptor-subtype selective agonists of the melanocortin-4 (MC-4R) receptor.
It is another object of the present invention to provide piperazine urea derivatives which are receptor-subtype selective partial agonists of the melanocortin-4 (MC-4R) receptor.
It is another object of the present invention to provide pharmaceutical compositions comprising the melanocortin-4 receptor agonists of the present invention with a pharmaceutically acceptable carrier.
It is another object of the present invention to provide methods for the treatment or prevention of disorders, diseases, or conditions responsive to the activation of the melanocortin-4 receptor in a subject in need thereof by administering the compounds and pharmaceutical compositions of the present invention.
It is another object of the present invention to provide methods for the treatment, control, or prevention of obesity and diabetes mellitus by administering the compounds and pharmaceutical compositions of the present invention to a subject in need thereof.
These and other objects will become readily apparent from the detailed description that follows.